HIV-1 vaccine development programmes have sofar primarily focussed on the induction of VN antibodies, CD4+ T helper cell responses and CD8+ cytotoxic T cell (CTL) responses against the viral structure proteins. These efforts have resulted in limited success sofar. In recent years, increased attention has been paid to the induction of HIV-1 specific CTL responses, since it was shown that the development of such responses during primary infection in humans coincides with the decline in viral load. Furthermore, we have recently shown that shortly after primary infection, long term asymptomatic individuals (LTA) develop HIV-1 early protein (Rev and Tat) specific CTL responses whereas fast progressors fail to do so. Both LTA and fast progressors do develop equally high CTL responses against structural proteins (Gag and Pol). We obtained similar data in macaques infected with an infectious molecular clone of SIV (SIVmac32H J5). Collectively these data suggest that, early protein specific CTL protect more efficiently against SIV/HIV-1 disease progression than late protein specific CTL. On basis of these data we hypothesize that they will also protect more efficiently against challenge infection in vaccination experiments. We have recently obtained data in a pilot vaccination experiment, showing that SIV Rev and Tat specific CTL may indeed protect macaques against persistent infection after challenge infection. In the present project application we propose to substantiate our hypothesis by comparing the outcome of SIV challenge in macaques vaccinated with replicating vectors expressing early proteins versus late proteins. An ex vivo challenge model for the evaluation of candidate HIV-1 vaccines in human clinical trials may provide additional information about the actual ability of the immune response to protect from challenge infection. We have recently developed a human/macaque to mouse chimeric model the xeno-GvHD mouse model which we will evaluate as an ex vivo challenge model. In this model we will graft PBMC from the vaccinated macaques into immuno compromised mice and compare the outcome of challenge infection in the vaccinated macaques with challenge infection in the mice grafted with PBMC from the macaques.